Use of 4-phenyl-substituted tetrahydroisoquinolines in the treatment of pain, migraine headaches and urinary incontinence

Abstract

Provided herein are methods of using compounds of formula (IA-IF) that are aryl- and heteroaryl-substituted tetrahydroisoquinolines, for the treatment of chronic and neuropathic pain, the treatment and prevention of migraine headache, and the treatment of stress, urge and mixed urinary incontinence.

What is claimed is:  
     
         1 . A method of treating chronic or neuropathic pain, treating or preventing migraine headache, or treating urge, stress or mixed urinary incontinence comprising administration of an effective amount of a compound of formula IA-IF having the following structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 the carbon atom designated * is in the R or S configuration;  
 R 1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl, each of which is optionally substituted with 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3  alkyl, halogen, aryl, —CN, —OR 9  and —NR 9 R 10 ;  
 R 2  is H, C 1 -C 6  alky, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl or C 1 -C 6  haloalkyl;  
 R 3  is H, halogen, —OR 11 , —S(O)R 12 , —S(O) n NR 11 R 12 , —CN, —C(O)R 12 , —C(O)NR 11 R 12 , C 1 -C 6  alky, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, —O(phenyl) or —O(benzyl), wherein each of —O(phenyl) and —O(benzyl) is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy, or wherein R 3  is a C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl group, then said group is optionally substituted with from 1 to 3 substituents selected independently at each occurrence thereof from C 1 -C 3  alkyl, halogen, aryl, —CN, —OR 9  and —NR 9 R 10 ;  
 provided that for compounds of formula IA, R 3  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl, each of which is optionally substituted with from 1 to 3 substituents selected independently at each occurrence thereof from C 1 -C 3  alkyl, halogen, aryl, —CN, —OR 9  and —NR 9 R 10 ;  
 provided that for compounds of formula IB, R 3  is —O(phenyl), —O(benzyl), —OC(O)R 13  or —S(O) n R 12 , each of —O(phenyl) and —O(benzyl) is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy;  
 R 4  is H, halogen, —OR 11 , S(O) n R 12 , —S(O)NR 11 R 12 , —CN, —C(O)R 12 , —C(O)NR R 12 , —NR 11 R 12 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, O(phenyl) or —O(benzyl), wherein each of —O(phenyl) and —O(benzyl) is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl or C 1 -C 4  alkoxy and wherein R 4  is a C 1 -C 4  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl group, then said group is optionally substituted with from 1 to 3 substituents selected independently at each occurrence thereof from C 1 -C 3  alkyl, halogen, aryl, —CN, —OR 9  and —NR 9 R 10 ;  
 provided that for compounds of formula IC, R 4  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, or C 4 -C 7  cycloalkylalkyl, each of which is optionally substituted with from 1 to 3 substituents selected independently at each occurrence thereof from C 1 -C 3  alkyl, halogen, aryl, —CN, —OR 9  and —NR 9 R 10 , or R 5  and R 6  or R 6  and R 7  may be —O—C(R 2 ) 2 —O—; provided that for compounds of formula ID, R 4  is —O(phenyl), —O(benzyl), —OC(O)R 13 , —NR 11 R 12  or —S(O) n R 12 , each of —O(phenyl) and —O(benzyl) is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy;  
 R 5 , R 6  and R 7  in compounds of each of the formulae IA, IB, IC, ID, IE and IF are each independently H, halogen, —OR 11 , —S(O) n R 12 , —CN, —C(O)R 12 , —NR 11 R 12 , —C(O)NR 11 R 12 , —NR 11 C(O)R 12 , —NR 11 C(O) 2 R 12 , —NR 11 C(O)NR 12 R 13 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl, wherein each of R 5 , R 6  and R 7  is a C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl group, then said group is optionally substituted with from 1 to 3 substituents selected independently at each occurrence thereof from C 1 -C 3  alkyl, halogen, aryl, —CN, —OR 9  and —NR 9 R 10 , or R 5  and R 6  or R 6  and R 7  may be —O—C(R 12 ) 2 —O—;  
 provided that for compounds of formula IE at least one of R 5  or R 7  is fluoro, chloro, or methyl;  
 or R 7  and R 6  are each independently —O—C(R 12 ) 2 —O— in compounds of the formulae IE, but only where R 2  is fluoro, chloro or methyl;  
 or R 7  and R 6  can independently also be —O—C(R 12 ) 2 —O— in compounds of the formulae IE, but only where R 7  is fluoro, chloro or methyl;  
 R 8  is H, halogen, or OR 11 , provided that for compounds of formula IF, R 8  is halogen;  
 R 9  and R 10  are each independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxyalkyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, —C(O)R 3 , phenyl or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy;  
 or R 9  and R 10  are taken together with the nitrogen to which they are attached to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine;  
 R 11  is H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxyalkyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, —C(O)R 3 , phenyl or benzyl, where R 11  is a C 1 -C 4  alkyl, phenyl or benzyl group, then said group is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy;  
 R 12  is H, amino, C 1 -C 4  alkyl, (C 1 -C 4  alkyl)amino, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxyalkyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, phenyl or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl and C 1 -C 6  alkoxy;  
 or R 11  and R 12  are taken together with the nitrogen to which they are attached to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine;  
 provided that only one of R 9  and R 10  or R 9  and R 10  are taken together with the nitrogen to which they are attached to form piperldine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine;  
 R 13  is C 1 -C 4  alkyl, C 1 -C 4  haloalkyl or phenyl;  
 n is 0, 1, or 2, and;  
 aryl is phenyl which is optionally substituted 1-3 times with halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl and C 1 -C 4  alkoxy,  
 or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.  
 
     
     
         2 . A method of  claim 1 , wherein R 1  is C 1 -C 3  alkyl.  
     
     
         3 . A method of  claim 2 , wherein R 1  is CH 3 .  
     
     
         4 . A method of  claim 1 , wherein R 2  is H, C 1 -C 4  alkyl or C 1 -C 6  haloalkyl.  
     
     
         5 . A method of  claim 4 , wherein R 2  is H or CH 3 .  
     
     
         6 . A method of  claim 1 , wherein R 3  is H or R 3  is C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl, each of which is optionally substituted with from 1 to 3 substituents selected independently at each occurrence thereof from C 1 -C 3  alkyl, halogen, aryl, —CN, —OR 9  and NR 9 R 10 , or R 3  is —O(phenyl) or —O(benzyl) optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy.  
     
     
         7 . A method of  claim 6 , wherein R 3  is methyl, ethyl, propyl, or isopropyl.  
     
     
         8 . A method of  claim 6 , wherein R 3  is —O(phenyl) or —O—CH 2 — (phenyl), each of which is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy.  
     
     
         9 . A method of  claim 6 , wherein R 3  is H.  
     
     
         10 . A method of  claim 1 , wherein R 4  is H, or R 4  is —NR 11 R 12  or R 4  is C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl, each of which is optionally substituted, or wherein R 4  is —O(phenyl) or —O(benzyl), each of which is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy.  
     
     
         11 . A method of  claim 10 , wherein R 4  is methyl, ethyl, propyl, or isopropyl.  
     
     
         12 . A method of  claim 10 , wherein R 4  is —O(phenyl) or —O(CH 2 )phenyl, each of which is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy.  
     
     
         13 . A method of  claim 10 , wherein R 4  is H.  
     
     
         14 . A method of  claim 1 , wherein R 3  and R 4  are each H or wherein R 3  and R 4  are each halogen.  
     
     
         15 . A method of  claim 1 , wherein one of R 3  and R 4  is H and the other is CH 3 .  
     
     
         16 . A method of  claim 1 , wherein R 5 , R 6  and R 7  are each H, halogen, —OR 11 , —NR 11 R 12 , C 1 -C 6  alkyl and substituted C 1 -C 6  alkyl.  
     
     
         17 . A method of  claim 16 , wherein R 5 , R 6  and R 7  are each H.  
     
     
         18 . A method of  claim 16 , wherein one of R 5  or R 7  is F, Cl or Me and the other of R 5  or R 7  and R 6  are H, halogen, —OR 11 , —NR 11 R 12 , or optionally substituted C 1 -C 6  alkyl.  
     
     
         19 . A method of  claim 18 , wherein R 5  is F, Cl or Me; and R 7  is H.  
     
     
         20 . The method of  claim 18 , wherein R 5  is F, Cl or Me; and R 6  is H.  
     
     
         21 . A method of  claim 1 , wherein R 8  is halogen.  
     
     
         22 . A method of  claim 21 , wherein R 8  is fluoro.  
     
     
         23 . A method of  claim 1 , wherein: 
 R 1  is C 1 -C 3  alkyl;    R 2  is H, C 1 -C 4  alkyl or C 1 -C 6  haloalkyl;    R 3  is C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl, each of which is optionally substituted, or R 3  is —O(phenyl) or —O(benzyl), each of which is optionally substituted, or R 3  is H; R 4  is H, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl or C 4 -C 7  cycloalkylalkyl, each of which is optionally substituted with from 1 to 3 substituents selected independently at each occurrence thereof from C 1 -C 3  alkyl, halogen, aryl, —CN, —OR 9  and —NR 9 R 10 , or R 4  is —NR 11 R 12 , —O(phenyl) or —O(benzyl), wherein said —O(phenyl) or —O(benzyl), is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy;    or R 3  and R 4  are each halogen;    R 5 , R 6  and R 7  are each H, halogen, —OR 11 , —NR 11 R 12 , optionally substituted C 1 -C 6  alkyl or one of R 5  and R 7  is Cl, F or Me and the other of R 5  and R 7  and R 6  is H, halogen, —OR 11 , —NR 11 R 12 , C 1 -C 6  alkyl or substituted C 1 -C 6  alkyl.    
     
     
         24 . A method of  claim 23 , wherein: 
 R 1  is CH 3 ;    R 2  is H or CH 3 ;    R 3  is H, F, methyl, ethyl, propyl, isopropyl, —O(phenyl) or —O—CH 2 -(phenyl), wherein said —O(phenyl) or —O—CH 2 -(phenyl) is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy;    R 4  is H, F methyl, ethyl, propyl, isopropyl, —O(phenyl) or —O—CH 2 — (phenyl), wherein said —O(phenyl) or —O—CH 2 — (phenyl) is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy;    R 5 , R 6  and R 7  are each H or R 5  is F, CI or Me, or one of R 6  or R 7  is H and the other of R 6  and R 7  is halogen, —OR 11 , —NR 11 R 12 , or optionally substituted C 1 -C 6  alkyl.    
     
     
         25 . A method of  claim 23 , wherein R 8  is halogen.  
     
     
         26 . A method according to  claim 1 , wherein the carbon atom designated * is in the R configuration.  
     
     
         27 . A method according to  claim 1 , wherein the carbon atom designated * is in the S configuration.  
     
     
         28 . A method comprising a mixture of stereoisomeric compounds of  claim 1  wherein the carbon atom designated * is in the S or R configuration.  
     
     
         29 . A method according to  claim 1 , wherein the compound is selected from the group: 
 2,7-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-methoxy)phenyl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline.    2,7-dimethyl-4-(4-fluoro)phenyl-1,2,3,4-tetrahydroisoquinoline;    2,7-dimethyl-4-(3-fluoro)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-difluoro)phenyl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline;    2,7-dimethyl-4-(4-fluoro-3-methyl)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro-4-fluoro)phenyl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro)phenyl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline;    2,7-dimethyl-4-(4-methyl)phenyl-1,2,3,4-tetrahydroisoquinoline;    2,7-dimethyl-4-(3-fluoro-4-methyl)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-chloro)phenyl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-chloro-3-fluoro)phenyl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-dichloro)phenyl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline;    7-ethyl-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-difluoro)phenyl-7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    7-fluoro-4-(4-methoxy)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    7-fluoro-4-(3-fluoro-4-methoxy)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    7-fluoro-4-(3-fluoro-4-methyl)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    7-fluoro-4-(4-chloro-3-fluoro)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-difluoro)phenyl-7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro)phenyl-7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline;    7-cyano-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    2-methyl-4-phenyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline;    4-phenyl-1,2,7-trimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-chloro)phenyl-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-difluoro)phenyl-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-phenyl-2,7,8-trifluoromethyl-1,2,3,4-tetrahydrolsoquinoline;    2,7-dimethyl-8-fluoro-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    2,8-dimethyl-7-fluoro-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    2,7-dimethyl-8-methoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    2,7-dimethyl-8-hydroxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    2-methyl-4-phenyl-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-difluoro)phenyl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-fluoro-3-methyl)phenyl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-fluoro-4-methyl)phenyl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    7-methoxy-4-(3-methyl)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    2-methyl-7-phenoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    7-(4-methoxy)phenoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    7-benzyloxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    7-hydroxy-2-methyl-4-(3-methyl)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-fluoro-4-methyl)phenyl-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-fluoro-3-methyl)phenyl-7-hydroxy-2-methyl-1,2,3,4-tetrahydrolisoquinoline;    4-(3,4-difluoro)phenyl-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-cyano)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    2,8-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    2,8-dimethyl-4-(4-fluoro)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-difluoro)phenyl-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,5-difluoro)phenyl-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline;    2,8-dimethyl-4-(3-fluoro)phenyl-1,2,3,4-tetrahydroisoquinoline;    2,8-dimethyl-4-(4-fluoro-3-methyl)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro-4-fluoro)phenyl-2,8-dimethyl-1,2,3,4-tetrahydrolsoquinoline;    4-(3,4-dichloro)phenyl-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro)phenyl-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-chloro)phenyl-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-chloro-3-fluoro)phenyl-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline;    2,8-dimethyl-4-(4-methoxy)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-cyano)phenyl-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline;    2,8-dimethyl-4-(4-trifluoromethyl)phenyl-1,2,3,4-tetrahydroisoquinoline;    2,8-dimethyl-4-(4-methyl)phenyl-1,2,3,4-tetrahydroisoquinoline;    2-methyl-8-(N-methylamino)methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    8-(hydroxy)methyl-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    2-methyl-4-phenyl-8-sulfonamide-1,2,3,4-tetrahydroisoquinoline;    2-methyl-8-(N-methyl)sulfonamide-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    8-methoxy-2-methyl-4-(4-methyl)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,5-difluoro)phenyl-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro)phenyl-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-dichloro)phenyl-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-chloro-3-fluoro)phenyl-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro-4-fluoro)phenyl-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,5-difluoro)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro-5-fluoro)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,5-difluoro)phenyl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro-5-fluoro)phenyl-2,7-dimethyl-1,2,3,4-tetrahydrolsoquinoline;    2-methyl-4-(3,4,5-trifluoro)phenyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-fluoro)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoiine;    4-(3-fluoro-4-methyl)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-fluoro-3-methyl)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3,4-difluoro)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-chloro-3-fluoro)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-chloro-4-fluoro)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(3-cyano)phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-acetanilide)-2-methyl-1,2,3,4-tetrahydroisoquinoline;    4-(4-chloro)phenyl-4-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline;    (3,5-difluoro)-4-phenyl-1,2,7-trimethyl-1,2,3,4-tetrahydroisoquinoline;    (8-fluoro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-N-methylmethanamine;    (2-methyl-4-phenyl-7-isoquinolinyl)-N-methylmethanamine;    N-methyl-(2-methyl-4-phenyl-7-isoquinolinyl)-N-methylmethanamine;    8-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile;    (2-methyl-4-phenyl-1,2,3,4-tetrahydro-7-isoquinolinyl)methanol; and    2-ethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; and    an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.